scholarly journals A Pilot Prospective Single-Arm Clinical Study on Decitabine Plus CAG or IA Followed with HLA-Mismatched Nonmyeloablative Transplantation (micro transplantation) on De Novo Elderly Acute Myeloid Leukemia and Int-2/High Risk Myelodysplastic Syndrome Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2188-2188 ◽  
Author(s):  
Jie Sun ◽  
Yan Huang ◽  
Weijia Huang ◽  
Lizhen Liu ◽  
Jimei Ge ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Clinical Study ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Elderly Aml ◽  
Acute Myeloid

Abstract Objective: To observe the efficacy and safety of Decitabine plus CAG or IA followed with HLA-mismatched nonmyeloablative transplantation (micro transplantation) on de novo elderly Acute Myeloid Leukemia and Int-2/high risk Myelodysplastic Syndrome patients Methods: Till submission of this article, 10 patients were enrolled in this prospective clinical study. Patients were admitted from January 2017 to June 2018 to our centre. 6 of whom were elderly AML (≥60 years) and 4 were Int-2/high risk MDS according to IPSS-R scoring system. Induction chemotherapy were decitabine (15 mg/m2) for 5 days followed with CAG (cytarabine 10 mg/m2 q12h; aclarubicin 10 mg/day and G-CSF at 300 μg/day x 6 days for AML and 4 days for MDS), then followed with a transfusion of HLA-mismatched (≤7/10 matched HLA loci) related donor peripheral stem cells (micro transplantation) 24 hours after chemotherapy. Consolidation therapy was another 3 courses of chemotherapies which were decitabine (15 mg/m2) for 5 days with IA (3+7) for AML or CAG (6 days) for MDS, followed by micro transplantation 24 hours after each course. Till now, the total observable treatment courses were 21. Results: The average age of the patients was 63.5 years (range from 55 to 71 years). The average number of transfusion mononuclear cells (MNC) at per course was 3.26 (1.87-5.25) x 108/kg, the average CD34+ cells was 1.12 (0.34-3.16) x 106/kg, and the average of CD3+ T cells was 3.93 (1.87-7.17) x 107/kg. Among them, 5 cases (50%) obtained CR (CR+CRi), 3 cases obtained PR (30%). The ORR was 83.3% for elderly AML patients, 75% for MDS patients and 80% for all patients. The median recovery time of neutrophil (from the end of chemo to neutrophil ≥0.5 x 109) was 9 days and was 8.5 days for platelets (from the end of chemo to platelets ≥20 x 109). 1 patient developed severe aGVHD and died, 1 patient died of heart failure, no other serious adverse events were observed in rest patients. 7 of 10 cases developed peripheral T cell increase after stem cell transfusion, including the total CD3+ T cells, CD4+ and CD8+ T cells, with an average peak at day7. The increased T cells were verified as host origin by short tandem repeat (STR) detection performed on 1 patient. 8 of 10 cases occurred cytokine related fever (CRF) after stem cell transfusion. The fever was usually happened within 24 hours after stem cell transfusion, with an average duration of 5 days and a mean peak temperature at 39.7 ℃. With CRF there was an increase of cytokines with different patterns in different patients but majorly on IL-6, IL-2, IFN-r and TNF-a. Also there was an increase of C-Reactive Protein (CRP) which reached an average peak level as 116.9 mg/L. Patients with CRF had a CR+CRi rate at 62.5%. Conclusion: Our preliminary results of this study indicate that Decitabine plus CAG or IA followed with micro transplantation have an ORR at 80% in de novo elderly Acute Myeloid Leukemia and Int-2/high risk Myelodysplastic Syndrome patients with controllable recover time of neutrophils and platelets. Although the incidence of acute graft versus host disease (aGVHD) in micro transplantation was as low as 1-2% according to reports, it is still possible. How to predict and avoid severe aGVHD is still under investigate. The presence of cytokine related fever may associate with the increase of hosts' T cells, which may relate to the improvement of therapeutic response. Larger cohorts and more investigates need to be done to clarify above findings. Disclosures No relevant conflicts of interest to declare.

scholarly journals Non-Ablative Chemotherapy Followed by HLA-Mismatched Allogeneic CD3+ T-Cells Infusion Causes An Augment of T-Cells With Mild CRS: A Multi-Centers Single-Arm Prospective Study on Elderly Acute Myeloid Leukemia and int-2/High Risk Myelodysplastic Syndrome Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Huang ◽  
Minghua Hong ◽  
Zhigang Qu ◽  
Weiyan Zheng ◽  
Huixian Hu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
T Cells ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Overall Survival Rates ◽  
Acute Myeloid

ObjectiveTo evaluate the efficacy and safety of standard or low-dose chemotherapy followed by HLA-mismatched allogeneic T-cell infusion (allo-TLI) for the treatment of elderly patients with acute myeloid leukemia (AML) and patients with intermediate-2 to high-risk myelodysplastic syndrome (MDS).MethodsWe carried out a prospective, multicenter, single-arm clinical trial. Totally of 25 patients were enrolled, including 17 AML patients and 8 MDS patients. Each patient received four courses of non-ablative chemotherapy, with HLA-mismatched donor CD3+ allo-TLI 24 h after each course. AML patients received chemotherapy with decitabine, idarubicin, and cytarabine, and MDS patients received decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor.ResultsA total of 79 procedures were performed. The overall response rates of the AML and MDS patients were 94% and 75% and the 1-year overall survival rates were 88% (61–97%) and 60% (13–88%), respectively. The overall 60-day treatment-related mortality was 8%. Compared with a historical control cohort that received idarubicin plus cytarabine (3 + 7), the study group showed significantly better overall response (94% vs. 50%, P=0.002) and overall survival rates (the 1-year OS rate was 88% vs. 27%, P=0.014). Post-TLI cytokine-release syndrome (CRS) occurred after 79% of allo-TLI operations, and 96% of CRS reactions were grade 1.ConclusionElderly AML patients and intermediate-2 to high-risk MDS patients are usually insensitive to or cannot tolerate regular chemotherapies, and may not have the opportunity to undergo allogeneic stem cell transplantation. Our study showed that non-ablative chemotherapy followed by HLA-mismatched allo-TLI is safe and effective, and may thus be used as a first-line treatment for these patients.Clinical Trial Registrationhttps://www.chictr.org.cn/showproj.aspx?proj=20112.

scholarly journals Outcomes of Haploidenitical Stem Cell Transplants for De Novo Acute Myeloid Leukemia, Myelodysplastic Syndrome and Acute Myeloid Leukemia Arising from MDS: The MD Anderson Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3225-3225
Author(s):  
Reshma Ramlal ◽  
Sameh Gaballa ◽  
Julianne Chen ◽  
Gabriela Rondon ◽  
Betul Oran ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
De Novo ◽  
De Novo Aml ◽  
Disease Free ◽  
Active Disease ◽  
Acute Myeloid

Abstract Background Outcomes of haploidentical stem cell transplantation (haploSCT) have improved since the introduction of post-transplantation cyclophosphamide (PTCy) to the extent that survival is comparable to HLA matched donor transplantation. Here, we report the outcomes of 80 patients treated at our institution for de novo acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and AML arising from MDS treated with melphalan, fludarabine conditioning. Methods We retrospectively analyzed data from 80 patients (60 [75%] with de novo AML and 20 [25%] with MDS or MDS/AML who received a haploSCT between 2009 to April 2015. Twenty-nine patients (38%) in total had adverse cytogenetics while 12/18 (66%) of MDS, MDS/AML patients had adverse cytogenetics. Fifty one patients (64%) were in a complete response (CR) at the time of transplant. Thirty-seven patients (46.3%) were conditioned with fludarabine 40 mg/m2 (day -6 to -3), melphalan 100 mg/m2 (day -8), thiotepa 5 mg/kg (day -7), 26 (32.5%) with fludarabine and melphalan 140 mg/m2 and 13 (16%) with fludarabine, melphalan and total body irradiation (TBI) at 200 cGy. Graft vs host disease (GvHD) prophylaxis consisted of PTCy on day +3 and +4 after haploSCT and tacrolimus and mycophenolate for 6 and 3 months, respectively. Donors included children (48%), siblings (41%) and parents (10%). Seventy six patients (95%) received a bone marrow graft and the remaining 4 (5%) received peripheral blood. Results Median age was 50 years (range, 15-69 years), 54% were male. Three patients had early death: 2 from infection and 1 from multiorgan failure. Of the 77 evaluable patients, 76 engrafted (99% primary engraftment). The median times to neutrophil and platelet engraftment were 18 days (range, 6-40 days) and 25 days (range, 10-54 days), respectively. The rates of grade II-IV and III- IV acute GvHD at day 100 were 30% and 3%, respectively. Chronic GvHD occurred in 8 of 60 patients (13%): 3 with extensive and 5 with limited stage. At the last follow-up, 40 patients (50%) were alive and disease-free. Relapse occurred in 17 of the 60 patients with de novo AML (28.3%) and 6 of 20 patients with MDS, MDS/AML (30%). The 1-year and 2-year overall survival rates were 56% and 47.5%, respectively, with 64.6% of patients in CR1 or 2 at the time of transplant and 42.3% of patients with active disease or greater than CR2 alive at 1 year (log rank p= 0.030). On univariate analysis, cytogenetic risk and disease status prior to transplant were found to have a statistically significant influence on progression free survival (PFS) (Figure 1B, C) All 17 patients with active disease at the time of transplant attained a CR and 7 (41%) remained disease free and alive at the median time of follow-up. The cumulative incidence of non-relapse mortality (NRM) at day 100 and 1 year were 13.8% and 27.4% respectively. Of the 34 deaths; 18 (53%) were due to relapsed disease, 7(20%) infection, 3 GvHD, 5 organ failure and 1 graft failure. Conclusion HaploSCT using a fludarabine, melphalan backbone for conditioning is safe and effective not only for patients with de novo AML, but also with MDS and AML arising from MDS. Improvement in relapse rate for patients with high-risk disease and those not in remissions at transplant is warranted. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

DNMT3a Mutations Define a Pre-Leukemic Stem Cell Reservoir In Human Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 487-487 ◽  
Author(s):  
Liran I. Shlush ◽  
Sasan Zandi ◽  
Amanda Mitchell ◽  
Weihsu Claire Chen ◽  
McLeod Jessica ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Allele Frequency ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clonal Expansion ◽  
Genetic Alterations ◽  
Npm1 Mutation ◽  
Acute Myeloid

Abstract Leukemia in humans arises from the multistep accumulation of mutations. However, the identity of the cell of origin, the nature of the first genetic lesion and the order of subsequent mutations remain poorly understood, as most cases of de novo acute myeloid leukemia (AML) are diagnosed without prior observation of a pre-leukemic clonal expansion. As part of studies to examine intra-tumoral genetic heterogeneity in AML, we carried out deep targeted sequencing (read depth 250×) of 101 commonly mutated leukemia genes on samples from 12 patients at diagnosis. Normal T-cells from each sample were expanded in vitro to provide a non-leukemic hematopoietic tissue for comparison. In 3 of 4 patients, we unexpectedly identified DNMT3a mutation not only in AML cells but also in T-cells at a low allele frequency (1-20%). Other genetic alterations such as NPM1 mutation (mutNPM1) were found only in AML cells and not in T-cells, ruling out contaminating AML cells as the source of the DNMT3a signal in cultured T-cells. To investigate the prevalence of T cell involvement, an additional 71 samples from AML patients at diagnosis were screened by Sanger sequencing for DNMT3a mutations. 17 of 71 AML samples (24%) carried R882 codon mutations (mutDNMT3a), and 15 of 17 (88%) also carried mutNPM1. Mutant allele frequency in freshly isolated T-cells was measured by droplet digital PCR (ddPCR). mutDNMT3a with no evidence of mutNPM1 was detected in T-cells of 12 of 17 patients (70.5%), suggesting that DNMT3a mutation occurs before NPM1 mutation in an ancestral stem/progenitor cell that gives rise to both T-cells and the dominant AML clone present at diagnosis. To directly determine whether phenotypic stem/progenitor cells that carried the mutDNMT3a allele could be identified within the non-leukemic hematopoietic compartment of AML blood and bone marrow samples, we undertook genetic analysis of highly-resolved phenotypically-defined normal stem, progenitor and mature lymphoid cell fractions from 10 patient samples. mutDNMT3a without detectable mutNPM1was present in stem cells and all downstream progenitors, with mean allele frequency among multipotent progenitor (MPP), multilymphoid progenitor (MLP) and common myeloid progenitor (CMP) of 31.7%. mutDNMT3a and mutNPM1 were found together only in granulocyte monocyte progenitor (GMP) and CD33+ blasts. Importantly, even for patients in whom mutDNMT3a was not detected in mature lymphoid populations, mutDNMT3a without mutNPM1 was found in MPP, MLP, CMP, providing strong evidence that mutDNMT3a precedes mutNPM1 during leukemogenesis. Analysis of diagnostic and remission samples revealed similar or higher proportion of cells with mutDNMT3a alone at remission compared to diagnosis. Xenotransplantation of cells from the diagnostic samples of 2 patients with mutDNMT3a and mutNPM1generated predominantly non-leukemic multilineage grafts (18 of 19 mice) with predominance of cells bearing mutDNMT3a without mutNPM1 (mean allele frequency 57%), confirming that mutDNMT3a was present in HSC. Kinetic analysis at 8 and 16 weeks revealed increasing mutDNMT3a allele frequency in multilineage xenografts over time, suggesting that mutDNMT3a confers a competitive growth advantage over non-mutated HSC. Collectively, our results are consistent with the clonal expansion in AML patients of mutDNMT3a HSC that survive chemotherapy. These cells may therefore represent a reservoir for further genomic progression leading to relapse. Our findings now offer the possibility of therapeutic intervention during remission to eliminate these surviving pre-leukemic clones and prevent relapse in a large proportion of AML patients carrying mutDNMT3a. As well, our work provides a framework for the identification of other early events in leukemogenesis and examination of how these changes disrupt normal HSC function and lead to leukemia. Disclosures: Wang: Trillium Therapeutics/Stem Cell Therapeutics: Research Funding.

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